Modification of the RANKL-RANK-binding site for the immunotherapeutic treatment of osteoporosis

Here, we proposed the use of mutated RANKL as an immunogen for active immunization and to induce anti-cytokine antibodies for osteoporosis treatment. Introduction Osteoclasts are responsible for bone resorption in bone-related disorders. Anti-cytokine therapeutic antibodies such as denosumab are effective for the treatment of osteoporosis. However, problems with antibody manufacturing and the immunogenicity caused by multiple antibody doses have led to the use of auto-cytokines as immunogens to induce anti-cytokine antibodies. Methods RANKL was point-mutated based on the crystal structure of the complex of RANKL and its receptor RANK. Results As a proof of concept, immunization with RANKL produced high levels of specific antibodies and blocked osteoclast development in vitro and inhibited osteoporosis in RANKL-treated or ovariectomized mouse models. Conclusions The results demonstrate the successful use of mutated RANKL as an immunogen for the induction of anti-RANKL immune response. This strategy is useful in general anti-cytokine immunotherapy to avoid toxic side effects of osteoporosis treatment.